Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients.

• Background: p21-activated kinase 1 (Pak1) phosphorylates many proteins in both normal and transformed cells. Its ability to phosphorylate and thereby activate the estrogen receptor alpha (ER alpha) potentially limits the effectiveness of antiestrogen treatment in breast cancer. Here we studied associations between Pak1 expression and subcellular localization in tumor cells and tamoxifen resistance. Methods: Pak1 protein expression was evaluated in 403 primary breast tumors from premenopausal patients who had been randomly assigned to 2 years of adjuvant tamoxifen or no treatment. Tamoxifen response was evaluated by comparing recurrence-free survival in relation to Pak1 and ER alpha expression in untreated versus tamoxifen-treated patients. Tamoxifen responsiveness of human MCF-7 breast cancer cells that inducibly expressed constitutively active Pak1 or that transiently overexpressed wild-type Pak1 (Wt-Pak1) or Pak1 that lacked functional nuclear localization signals (Pak1 Delta NLS) was evaluated by analyzing cyclin D1 promoter activation and protein levels as markers for ER alpha activation. The response to tamoxifen in relation to Pak1 expression was analyzed in naturally tamoxifen-resistant Ishikawa human endometrial cancer cells. All statistical tests were two-sided. Results: Among patients who had ER alpha-positive tumors with low Pak1 expression, those treated with tamoxifen had better recurrence-free survival than those who received no treatment (hazard ratio [HR] = 0.502, 95% confidence interval [CI] = 0.331 to 0.762; P = .001) whereas there was no difference in recurrence-free survival between treatment groups for patients whose tumors had high cytoplasmic (HR = 0.893, 95% CI = 0.420 to 1.901; P = .769) or any nuclear Pak1 expression (HR = 0.955, 95% CI = 0.405 to 2.250; P = .916). In MCF-7 cells, overexpression of Wt-Pak1, but not of Pak1 Delta NLS, compromised tamoxifen response by stimulating cyclin D1 expression. Treatment of Ishikawa cells with tamoxifen led to an increase in the amount of nuclear Pak1 and Pak1 kinase activity, suggesting that tamoxifen, to some extent, regulates Pak1 expression. Conclusions: Our data support a role for Pak1, particular Pak1 localized to the nucleus, in ER alpha signaling and in tamoxifen resistance.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

Predictive Value of Tests

Phosphorylation

Neoplasm Staging

Middle Aged

Hormonal: pharmacology

Antineoplastic Agents

Adult

Hormonal: therapeutic use

Blotting

Tumor

Cell Line

Breast Neoplasms: therapy

Breast Neoplasms: prevention & control

Breast Neoplasms: pathology

Breast Neoplasms: chemistry

Western

Disease-Free Survival

Neoplasm

Drug Resistance

Female

Estrogen Receptor alpha: metabolism

Estrogen Receptor alpha: drug effects

Estrogen Antagonists: therapeutic use

Estrogen Antagonists: pharmacology

Gene Expression Regulation

Follow-Up Studies

Microscopy

Immunohistochemistry

Humans

Neoplastic

Confocal

Fluorescence

Protein-Serine-Threonine Kinases: analysis

Randomized Controlled Trials

Research Support

N.I.H.

Extramural

Non-U.S. Gov't

Tamoxifen: pharmacology

Tamoxifen: therapeutic use

Tumor Markers

Biological: analysis

Premenopause

Protein Array Analysis

Prognosis

MEDICINE

Publication and Content Type

art (subject category)

ref (subject category)